The human microbiome is a microbial community, which can be described as the sum of all microbial life living in or on specific sites of the human body. Recent advances in DNA sequencing techniques have facilitated more in-depth analysis of the microbiomes of the gut, skin, genito-urinary tract and the lung, revealing a microbial super organ residing symbiotically with host mucosal surfaces. It is becoming better appreciated that the composition and activity of the microbiome has significant metabolic, nutritional and immunological effects on the host (1). The microbiome evolves within a host from birth, constantly being fine-tuned to maintain a homeostatic balance with the host's immune system. This evolution is influenced by host factors, such as the adaptive and innate immune responses, external factors such as diet, medication and toxin exposure, and illness.
The gastrointestinal tract has the greatest number and diversity of microbes, with approximately 100 trillion microbes residing in the gut (2 to 10 times the total number of human cells in the entire body), while the collective genomes of the gut microbiome contain approximately 100 times more genes than the human genome. These microbes are highly adapted to survive within complex community structures, requiring nutrients from other microbes and/or host processes. Interestingly, using sequencing approaches, over 1,000 different bacterial species have been identified within the gut microbiome. However, a specific individual's microbiome typically contains only 300-500 different species, leading to enormous inter-individual variability in microbiome composition. This variability is even more pronounced when patients with diseases, such as inflammatory bowel disease, are compared to healthy individuals, supporting the concept that an imbalance of certain microbes (i.e. dysbiosis) within the microbiome may contribute to aberrant inflammatory and metabolic responses (2). Similarly, alterations in the microbiome of the lung have been associated with lung-associated disorders such as asthma and chronic obstructive pulmonary disease (3).
The microbiome supports the development of epithelial barrier function and integrity, while promoting potent tolerance and protective immune mechanisms within mucosal tissues (4). Microbes have direct effects on host immune responses and metabolites derived from microbial fermentation of nutrients within the gut not only contribute to host energy intake, but also significantly influence host immunological responses (e.g. short-chain fatty acids and histamine) (5, 6). Appropriate cellular and molecular networks involve innate pattern recognition receptor activation, T and B cell polarization and expansion, secretion of a wide range of effector and regulatory cytokines and host metabolites. Ultimately this trialogue between the microbiome, immune cells and tissue cells within the gut results in the establishment of optimal digestive capabilities, gut motility, immune tolerance to foods and certain microbial antigens, and protection against pathogens.
The immunological consequences of bacterial processes within the gastrointestinal tract have effects on organs distant to the gut itself (7). For example, respiratory inflammation has been treated in murine models by oral administration of certain probiotic bacteria such as Lactobacilli and Bifidobacteria (8, 9). In addition, a reduced gut bacterial diversity early in life increases the risk of later life asthma (10).
Akkermansia species are commensal microorganisms. They have been isolated from the microbial flora within the human gastrointestinal tract (11). The immune system within the gastrointestinal tract cannot have a pronounced reaction to members of this flora, as the resulting inflammatory activity would also destroy host cells and tissue function. Therefore, some mechanism(s) exist whereby the immune system can recognize commensal non-pathogenic members of the gastrointestinal flora as being different to pathogenic organisms.
This ensures that damage to host tissues is restricted and a defensive barrier is still maintained. Akkermansia muciniphila has been shown in a murine model to modulate pathways involved in establishing homeostasis for basal metabolism and immune tolerance toward commensal microbiota (12).
Akkermansia muciniphila has been previously reported to be reduced in faecal samples from obese individuals and patients with inflammatory bowel disease (13). Akkermansia muciniphila is associated with a healthier metabolic status and better clinical outcomes after a calorie restriction intervention in overweight/obese adults (14). Indeed, published International Patent Application WO 2014/075745, and published International Application WO 2014/076246 claiming priority therefrom, concern the protective effects of Akkermansia muciniphila in obese individuals and propose administration of Akkermansia muciniphila to individuals exhibiting obesity and/or metabolic disorders such as type 2 diabetes to provide various beneficial effects (15). Administration of Akkermansia muciniphilia to obese and type 2 diabetic mice has been shown to correlate with an improved metabolic profile and to be able to protect against high fat diet-induced metabolic disorders. Beneficial effects were reported of interest in relation to associated gut inflammation including increase of intestinal levels of endocannabinoids (16). However such studies provide no information relevant to ameliorating other forms of inflammation, including gut inflammation of different etiology.
It has now been discovered that Akkermansia muciniphila levels are decreased in non-obese asthma patients with uncontrolled symptoms and this bacterium is protective in non-obese animal models of respiratory inflammation. It has been previously described that the same bacterium exerts immunoregulatory effects within the gastrointestinal tract, possibly directly and indirectly via the digestion of intestinal mucins and subsequent effects on SCFA secretion by the microbiome (see again 12). Lower prevalence of Akkermansia muciniphila has also previously been correlated with IgE-mediated atopic disease in a small number of allergic children (17). However those studies provide no more than a mere correlation and provide no foundation for extrapolation of any beneficial effect of oral administration of the same microbe at a site remote from the gastrointestinal (GI) tract, nor evidence of a route by which this might be achieved.